Cryo-electron Microscopy Identifies Lethal Anthrax Protein Complex

Researchers identify key features in the anthrax protein complex
that facilitate entry into host cell.

The toxin protein complex found to act as a 'conveyor belt' for
bacterial entry.

The study provides insights into possible drug target.

Cryo-electron Microscopy Identifies Lethal Anthrax Protein Complex

The three dimensional structure of the anthrax toxin that facilitates its entry into the
cytoplasm of the cells have been published in a study in the the Journal of
General Physiology detailing how the toxin behaves as a 'conveyor belt' for
the entry of toxic enzymes into the cell.

‘Drug targets aimed at anthrax protein complex will control toxicity in anthrax.’

Molecular Basis for Anthrax

Bacillus anthracis causes anthrax. This spore
forming bacterium enters the animal or human and begins to rapidly attack the
immune cells. The bacterium secretes three types of toxins that aid in
overpowering the immune cells of the host;

Protective
Antigen (PA)

Lethal
Factor (LF)

Edema
Factor (EF)

The main targets of these toxins
are to attack the immune cells that ingest invading microorganisms like the
macrophages and other defensive cells.

Mode of Action

The three toxins are potent when they act
together, but are not toxic when they are present separately.

Function of

PA: The LF and EF have to combine
with PA to be lethal. It facilitates the entry of the other toxins into
the cell.

The three toxins combine to form a lethal
complex that results in the destruction of the host cells due to disruption in
many signaling pathways.

Mechanism of Entry into the Host Cell

The three toxins combine to form a prepore
complex that facilitates the entry of the toxin into the cell. This structure
was studied by McGill University's Dr. Isabelle Rouiller and Sanford Burnham
Prebys Medical Discovery Institute, Dr. Robert Liddington and colleagues using
a cryo-electron microscopy.

The Mechanism of Entry Known so Far

The PA, LF, EF complex bind to a receptor on
the surface of the host cell, while an enzyme secreted by the host cell cleaves
a portion of PA. The toxic complex then attach to six other PA molecules to
form a ring like structure. The host then engulfs this complex and takes the
toxin into the cell using endocytosis.

A bubble like structure takes the toxin into
the cell, where the toxin changes shape and then begins to attack the cell when
the endosome diffuses

Current Understanding of Toxin Entry Using
Cryo-electron Microscopy

The map provided by cryo-electron microscopy
found

7
PA were found around a narrow pore.

3
LF proteins were found at the rim of the pore.

Each
LF molecule was bound to the PA subunit and to its clockwise neighbour.

Functions of these Inter LF Interactions

Prevents the toxic enzymes from unfolding
prematurely.

Holds the toxic enzymes in place.

Mechanism of Entry Identified by
Cryo-electron Microscopy

When
the first LF molecule begins to enters the cell, the next LF molecule is
destabilized to facilitate its entry into the cell.

LF
molecules that are present in addition could then bind to the spots that
were vacated on the pore's rim. This will lead to a continuous entry of LF
molecules, as envision by electrophysiological studies.

Dr. Rouiller added "We have demonstrated
that the anthrax pore can translocate full-length LF in a highly efficient,
fast, and robust fashion. The pore can effectively remain fully loaded for
extended periods, acting as a conveyer belt while translocating a continuous
'daisy chain' of deadly LF molecules."

Bacillus anthracis is a rod shaped bacterium
that exists as spores when the conditions are not viable for its survival as a
normal cell. An individual is infected with anthrax when the spore is inhaled
into the body. The bacterium then rapidly divides from the spore with multiple
bacteria entering the blood stream.

The most important aspect of a bacterial
invasion by Bacillus anthracis is the secretion of the toxins, since antibiotic
therapy will clear the bacteria from the blood stream but not the toxins,
alternate drug targets that are aimed at the toxin is essential for control of
the disease and the symptoms produced. The mechanism of entry of the toxins
discovered through cryo-electron microscopy provides greater insight into
possible drug targets.

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